Background: Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to cancer. The group has developed genotyping assays for the "at-risk" variants of enzymes that protect against carcinogens in cigarette smoke, diet, industrial processes and environmental pollution. Following genotyping of over 5000 individuals for these candidate susceptibility genes, it has been found that the frequency of the at-risk genotypes for glutathione transferase M1 (GSTM1), theta 1 (GSTT1), Pi (GSTP1) and N-acetyltransferase (NAT1 and NAT2) vary significantly between Asians, Caucasian- and African-Americans. This suggests that some of the ethnic differences in cancer incidence may be due to genetic metabolic differences as well as exposure differences. Aims: In ongoing studies with researchers at the NIEHS, National Cancer Institute, Columbia Univ., Johns Hopkins Univ., Univ. of North Carolina and Univ. of Occupational and Environmental Health, Japan, the Genetic Risk Group (GRG) is testing the impact of these cancer susceptibility genes in case-control studies of cancer of the bladder, lung, liver, colon, stomach, prostate, and breast. Accomplishments: We have discovered that a variant allele of GSTP1 is associated with lower enzyme activity in lung tissue samples (8). We observed a role for glutathione transferase M1, T1, and P1 in breast cancer (10). It was found that both genetic and nutritional factors modulate levels of DNA damage observed among heavy smokers (1). The presence of the GSTT1 gene was determined to be a crucial factor in dichloromethane metabolism to formaldehyde in human liver (5). We helped to characterize newly discovered low activity alleles of the NAT1 gene (2). NAT1 and NAT2 were found to play a role in the development of bladder and oral cancer (14,15) but not, as previously observed, in breast cancers (12) We found that the NAT1*10 allele interacts with smoking exposure and NAT2 genotype in bladder cancer and that among smokers, this allele is associated with 2.8 to 26 fold increased risk for bladder cancer (14). Significance: These studies seek to integrate environmental and genetic factors in understanding the etiology of human disease.